Process for the preparation of alpha-halogeno-beta-methylvaleric acid derivatives



United States Patent 9 i This invention relates to a process for preparing ahalogeno-B-methylvaleric acid derivatives useful as an intermediate for production of isoleucine. Particularly, it relates to a process for preparing ot-halogeno-d-methylvaleric acid derivatives having the general formula wherein R is hydrogen, an alkylradical having from 3 to 8 carbon atoms such as propyl, n butyl, sec.-butyl, tertbutyl, n-amyl, i-amyl, hexyl, heptyl or octyl radical, a

phenyl substituted methyl radical such as monophenyla methyl, diphenylmethyl or. triphenylmethyl radical, menthyl radical orbornyl radical and X is bromine or iodine atom. v

Heretofore, it is known that oi-bromo-fi-methylvaleric' acid or esters thereof may be produced by reacting secbutyl halogenides with malouic acid or ester thereof in thepresence of sodium alcoholate followed by bromination and decarboxylation or by brominating fl-methyh valeric acid esters prepared from methylethylketone and monobromoacetic acid esters or hydrolysis product of the former esters. It is also known that a-bromo-B-methyl- Valerie acid or esters thereof obtained by aforementioned processes may be converted by reaction with potassium iodide to m-iodo-d-methylvaleric acid or esters thereof. These processes, however, are disadvantageous from the industrial point of view, because, for example, production of a-halogeno-B-methylvaleric acid derivatives by the processes involves a number of reaction steps to result in complicated modes of operation as well as in a long period of time for obtaining the desired product.

It is an object of this invention to provide a process capable of producing a-halogeno--methylvaleric acid der'ivatives having the aforementioned Formula I easily and in a short period of time without the above described disadvantages accompanied by the production according to known processes. Other objects of this invention will be apparent from the descriptions herein below.

a-Halogenofi-rhethylvaleric acid derivatives having the aforementioned general Formula I may be prepared by reacting erotonic acid derivatives having the general formula CH CH=CHCOOR 3,052,873 Patented Nov. 6, 1962 FCC These reactions may be chemically shown as follows:

CH;CH=CHCOOR (H) l CzHsMgX CH: O R

CHCH=C 02H OMgX' l Bromine or iodine Cg; X/O R /CH--CHC CzHs Y X OMgX Diluted mineral acid or saturated solution of ammonium chloride CH(!JH-C O O R In the above described equation X represents a halogen atom, R represents MgX' 'or the same alkyl radical having from 3 to 8 carbon-atoms, phenyl substituted methyl radical, menthyl radical or bornyl radical as defined above with R and X and R have the same meaningas above. i

Reaction of crotonic acid derivatives having the above described Formula II ,with ethylmagnesium halogenide is eflected by adding a solution of the above described crotonic acid derivative in an inert solvent such as ether, benzene or tetrahydrofuran dropwise to an ether solution of ethylmagnesium halogenide and allowing the resulting mixture to stand with stirring at temperature of about: 5 C. to about 34 C. The reaction is completedin' from about 30 min. to several hours. After completion: of the reaction, the reaction mixture is 'chilled at temperature below room temperature, for example, at 200" C. and to the chilled mixture is" added bromine or iodine in an amount as much as about 0.8-2.0 mol. per mol. of the above described crotonic. acid derivative, followed by stirring for a short period of time, for example, for about 10-30 min. to proceed reaction. Thereaction mixture is then poured into a mixture of ice and a diluted (about 5-10%) mineral acid suchas hydro-- chloric or sulfuric acid or a mixture of ice anda saturated solution of ammonium chloride; After comple-' tion of the reaction theorgani-c layer is isolated, Washed with water and dried. .From the driedorganic layer, is distilled off the solvent and the residue is distilled under; reduced pressure.

at-Halogeno-fi-methylvaleric acid derivatives having the above described general Formula I obtained bythe proc-:

ess according to the present invention may be converted:

acid with aqueous ammonia or by hydrolysis and subse quent reaction with aqueous ammonia of a-bIOmO-B-I methylvaleric acid esters. a-Iodo-fi-methylvaleric acid esters may be converted to isoleucine by subjecting the former to hydrolysis and reaction with aqueous am monia in the arbitrary order.

Examples of this invention are givenbelow. These examples, however, are to be understood as illustrative but not as limiting of the scope of this invention.

Example 1 A Grignard solution is prepared from 3 g. of metallic magnesium, 16 g. of ethyl bromide and 20 ml. of dry ether. A solution of 4.3 'g. of crotonic acid in 20 ml. of dry ether is added dropwise to the Grignard solution with stirring at room temperature. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to l C., followed by dropwise addition of 8 g. of dry bromine. The mixture is stirred for additional min. The resulting reaction mixture is poured into a mixture of ice and diluted hydrochloric acid and the organic layer separated is isolated. The organic layer is washed once with water and then with three portions of 10% solution of Na CO The alkaline layer thus obtained is acidified with 20% sulfuric acid with cooling and the organic layer is then extracted with ether. The ether extract is washed with water, dried over Na SO and subjected to distillation under reduced pressure to give 2.5 g. of a-bromo'B-methyl-valeric acid boiling at 138-139 C./20mm. Hg.

Example 2 To a Grignard solution prepared from 3 g. of metallic magnesium, 16 g. of ethyl bromide and 20 ml. of dry ether are added 50 mg. of cuprous chloride. As in Example 1, a solution of 4.3 g. of crotonic acid in 20 ml. of dry ether is dropwise added to the mixture with stirring, followed by reaction at room temperature for additional one hour. The resulting reaction mixture is chilled to C., followed by dropwise addition of 8 g. of dry bromine. The resulting mixture is treated in the same way as in Example 1 to give 3.2 g. of a-bromo-,8- methylvaleric acid boiling at 107-109 C./3 mm. Hg.

Example 3 A Grignard solution is prepared from 6 g. of metallic magnesium, 32.8 g. of ethyl bromide and 80 ml. of dry ether and 100 mg. of cuprous chloride is added to the solution. A solution of 14.2 g. of sec.-butyl crotonate in 80 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional 30 min. The resulting reaction mixture is chilled to -10 0., followed by dropwise addition of 27 g. of dry bromine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and diluted hydrochloric acid and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 16.6 .g. of secsbutyl a-bromo-}8-methyl-valeriate boiling at 8890 C./5 mm. Hg.

Analysis.Calcd. for C H O Br: C, 47.8; H, 7.57; Br, 33.14. Found: C, 47.93; H, 7.90; Br, 32.41.

Example 4 A Grignard solution is prepared from 8.4 g. of metallic magnesium, 42 g. of ethyl bromide and 160 ml. of dry ether and 150 mg. of of cuprous chloride is added to the solution. A solution of 20 g. of t-butyl crotonate in 100 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to -10 C., followed by dropwise addition of 40 g. of dry bromine. The mixture is stirred for additional 10 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried,

over Na SO and subjected to distillation under reduced pressure to give 13.9 g. of t-butyl a-bromo-fi-methyl valeriate boiling at 79-80 C./8 mm. Hg.

Analysis.-Calcd. for C H O Br: C, 47.8; H, 7.57; Br, 33.14. Found: C, 46.70; H, 7.27; Br, 32.58.

4 Example 5 A Grignard solution is prepared from 1.05 g. of metallic magnesium, 4.9 of ethyl bromide and 20 ml. of dry ether and 20 mg. of cuprous chloride is added to the solution. A solution of 4 g. of e-menthyl crotonate in 10 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional 2.5 hours. The resulting reaction mixture is chilled to 15 C., followed by dropwise addition of 5 g. of dry bromine. The mixture is stirred for additional one hour. The resulting reaction mixture is poured into a mixture of ice and diluted hydrochloric acid and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 2.9 g. of e-methyl a-bromo-p-methyl-valeriate boiling at 112-l13 C./0.2 mm. Hg.

Arzalysis.Calcd. for C H O Br: C, 57.7; H, 8.71; Br, 24.0. Found: C, 59.2; H, 8.94; Br, 23.32. [a] 48.70 (C=1.7 in ethanol).

Example 6 A Grignard solution is prepared from 1.78 g. of metallic magnesium, 8 g. of ethyl bromide and 32 ml. of dry ether and 75 mg. of cuprous chloride is added to the solution. A solution of 6.5 g. of a-bornyl crotonate in 30 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to 10 C., followed by dropwise addition of 11.7 g. of dry bromine. The mixture is stirred for additional 10 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 2.5 g. of d-bornyl a-bromo-p-methyl-valeriate boiling at -96 C./0.15 mm. Hg.

Analysis.Calcd. for C H O Br: C, 57.0; H, 8.16; Br. 24.2. Found: C, 57.93; H, 8.21; Br, 23.28. [1115: +18.95 (C=1.l6 in ethanol).

Example 7 A Grignard solution is prepared from 6.2 g. of metallic magnesium, 28 g. of ethyl bromide and 50 ml. of dry ether and 50 mg. of cuprous chloride is added to the solution. A solution of 8.6 of crotonic acid in 20 ml. of dry ether is added dropwise to the Grignard solution with stirring at room temperature. Stirring is continued for additional two hours. The resulting reaction mixture is chilled to -20 C., followed by portionwise addition of 25 g. of iodine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and diluted hydrochloric acid and the ether layer separated is isolated. The e her layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 7.6 g. of pale yellow liquid of u-iodo-fi-methyl-valeric acid boiling at -112" C./1 mm. Hg.

Analysis.-Calcd. for C H O I: C, 29.95; H, 4.54; I, 52.5. Found: C, 30.77; H, 4.94; I, 50.82.

Example 8 A Grignard solution is prepared from 8.4 g. of metallic magnesium, 42 g. of ethyl bromide and 160 ml. of dry ether and mg. of cuprous chloride is added to the solution. A solution of 20 g. of t-butyl crotonate in 100 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to -10 C., followed by portionwise addition of 64 g. of dry iodine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the other layer separated is isolated. The ether layer is washed with Na S O solution *NaHCO solution and water succcessively, dried over Na SO and subjected to distillation under reduced pressure to give 20.8 g. of t-butyl a-iodo-fi-methylvaleriate boiling at 7273 C./1 mm. Hg.

Analysis.Calcd. for C H O I: C, 40.3; H, 6.38; I, 42.6. Found: C, 40.24; H, 6.46; I, 42.4.

Example 9 A Grignard solution is prepared from 3.6 g. of metallic magnesium, 18 g. of ethyl bromide and 80 m1. of dry ether and 100 mg. of cuprous chloride is added to the solution. A solution or" 14.2 g. of sec.-butyl crotonate in 50 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to l() (3., followed by portionwise addition of 26 g. of dry iodine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the ether layer is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 18.8 g. of sec.-butyl or-iodofi-methylvaleriate boiling at Sit-81 C./0.8 mm. Hg.

Analysis.--Calcd. for O l-1 0 1: C 40.3; H, 6.38; I, 42.6. Found: C, 40.43; H, 6.53; I, 41.79.

Example 10 A Grignard solution is prepared from 5.25 g. of metallic magnesium, 25 g. of ethyl bromide and 180 ml. of dry ether and 100 mg. of cuprous chloride is added to the solution. A solution of 20 g. of e-menthyl crotonate in 50 ml. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to l0 C., followed by portionwise addition of 48 g. of dry iodine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 13.2 g. of e-menthyl a-iodo-;9-methylvaleriate boiling at- 110120 C./5 1O mm. Hg. (bath temperature).

AHLIIYSlSr-CfllCd. for CH29O2IZ C, H, I, 33.4. Found: C, 51.12; H, 7.31; I, 32.5. [a] 30.8 (C==1.9 in ethanol).

Example 11 A Grignard solution is prepared from l.78 g. of metallic magnesium, 8 g. of ethyl bromide and 32 ml. of dry ether and 75 mg. of cuprous chloride is added to the solution. A solution of 6.5 g. of d-bornyl crotonate in 30 mi. of dry ether is added dropwise to the Grignard solution with stirring under ice-cooling. Stirring is continued for additional one hour. The resulting reaction mixture is chilled to 10 (3., followed by portionwise addition of 20.5 g. of dry iodine. The mixture is stirred for additional 30 min. The resulting reaction mixture is poured into a mixture of ice and a saturated solution of ammonium chloride and the ether layer separated is isolated. The ether layer is washed with Na S O solution, NaHCO solution and water successively, dried over Na SO and subjected to distillation under reduced pressure to give 1.6 g. of d-bornyl oc-iodo-fi-rnethylvaleriate boiling at 125-135" C./8 10- mm. Hg (bath temperature).

5 Analysts-Calm. for C H o lz C, 50.8; H, 7.14; I, 33.6. Found: C, 52.1; H, 7.56; I, 32.18.

We claim: 1. A process for preparing a compound having the general formula wherein R is a member selected from the group consisting of hydrogen atom, alkyl radicals having from 3 to 8 carbon atoms, phenyl substituted methyl radicals, menthyl radical and bornyl radical and X is -a member selected from the group consisting of bromine and iodine which comprises reacting a compound having the general formula CH CH=CHCOOR wherein R has the same meaning as above with ethylm'agnesium halogenide, subjecting the reaction mixture to reaction with a halogen selected from the group consisting of bromine and iodine and treating the resulting reaction mixture with a hydrolyzing agent selected from the group consisting of diluted mineral acids and saturated solution of ammonium chloride.

2. A process for preparing a compound having the general formula wherein R is a member selected from the group consisting of hydrogen atom, alkyl radicals having from 3 to 8 carbon atoms, phenyl substituted methyl radicals, menthyl radical and bornyl radical and X is a member selected from the group consisting of bromine and iodine which comprises reacting a compound having the general formula CH CH=CHCOOR wherein R has the same meaning as above with ethylma gnesium halogenide in the presence of cuprous chloride, subjecting the reaction mixture to reaction with a halogen selected from the group consisting of bromine and iodine.

and treating the resulting reaction mixture with a hy drolyzing agent selected from the group consisting of diluted mineral acids and saturated solution of ammonium chloride.

3. A process for preparing a compound having the general formula wherein R is a member selected from the group consisting of hydrogen atom, alkyl radicals having from 3 to 8 carbon atoms, phenyl substituted methyl radicals, menthyl radical and bornyl radical which comprises reacting a compound having the general formula CH CH=CHCOOR openers wherein R is a member selected from the group consisting of hydrogen atom, alkyl radicals having from 3 to 8 carbon atoms, phenyl substituted methyl radicals, menthyl radical and bornyl radical which comprises reacting a compound having the general formula CH CH=CHCOOR wherein R has the same meaning as above with ethylmag- 8 nesium halogenide in the presence of cuprous chloride, subjecting the reaction mixture to reaction with iodine and treating the resulting reaction mixture with a yclrolyzing agent selected from the group consisting of diluted mineral acids and saturated solution of ammonium chloride.

No references cited. 

1. A PROCESS FOR PREPARING A COMPOUND HAVING THE GENERAL FORMULA 